Myelin deficiency is an X-linked neurological mutation in the md rat caused by a genetic defect in synthesis of proteolipid protein (PLP) in the CNS, resulting in arrested maturation and death of oligodendrocytes. In a new neutral mutation in the colony, LTS-md rats survive up to 2 months longer than the original md, allowing the study of the pathological changes associated with hypomyelination of axons. The life span of the md rat can also be extended by treatment with anticonvulsants. late axonal changes include focal axonal swellings and wrinkling of the axolemma. In the first specific aim, it is proposed to correlate morphological and biochemical studies on cell specific gangliosides for examination of the influence of demyelination on axons and astrocytes, and the effects of anticonvulsants. Preliminary studies showed an elevation of brain gangliosides which may be attributable to axonal reorganization in response to the maturational failure of oligodendrocytes. Further characterization of these gangliosides may yield important information with respect to glialaxonal interactions, relevant to multiple sclerosis and other demyelinating diseases. In addition to CNS changes, the md rat exhibits thymus degeneration, which is not seen in the LTS-md. Thymocyte maturation is sensitive to corticosteroid treatment, and the frequent seizures shortly before the death of the md mutant are shown to be accompanied by high serum cortisone levels. Cortisone- resistant thymocytes have a different ganglioside pattern than- sensitive cells. In the second specific aim, it is therefore proposed to examine T-cell subsets in the LTS-md, md, and cyclosporine- and cortisone-treated normal rats by flow cytometry, and correlate those findings to serum cortisone levels and ganglioside changes. Abnormalities in oligodendroglial and T-cell maturation appear to involve similar processes, which may be related to a functional ganglioside-PLP complex in their membrane. These studies should provide new insights regarding the relatioship of the immune system and CNS myelin deficiency, important for the neurological autoimmune and demyelinating diseases.
